In collaboration with 10 academic centers across the United States, we have recruited a large sample of families in which at least 2 siblings suffer from bipolar disorder or related mood disorders. This is the largest sample ever to participate in a genetic study of bipolar disorder. All research participants have undergone a diagnostic interview and provided a blood sample for DNA analysis. Genetic linkage studies have been performed using molecular markers evenly spaced across all chromosomes. These studies suggested several chromosomal regions may contain genes that contribute to bipolar disorder in these families. Ongoing work is aimed at identifying the actual genes involved. Using the latest genotyping chip technology and DNA pooling, we conducted the first genome-wide association study of bipolar disorder. The results implicated several genes, each of small effect, suggesting that bipolar disorder is a polygenic disease. Meta-analysis of independent case-control studies of bipolar disorder supported association with several distinct genes that play a role in zinc metabolism (SLC39A3), cell adhesion (JAM3), and maintenance of normal neuronal functioning (ANK3). During the past year, we have begun functional studies of the implicated genes and markers. We have found that the JAM3 variant affects expression of this gene in the brain, suggesting that the amount of JAM3 protein in brain may mediate risk for bipolar disorder. We have also found evidence that 2 independent regions of the ANK3 gene are risk factors for bipolar disorder. Other meta-analyses have been designed to detect genes that play a role not only in bipolar disorder, but also in related conditions such as major depression and attention-deficit hyperactivity disorder. Using this approach, we recently found a cluster of closely-related markers on chromosome 3 that play a role in both bipolar disorder and major depression. The markers lie in a region with many genes, so our first task in following up this finding is to identify which of the genes is actually involved. In collaboration with other investigators at the NIMH Intramural Program, we have also investigated neuroimaging measures that have been associated with bipolar disorder and may reveal biological aspects of the disease. We have carried out candidate gene and genome-wide association studies of serotonin-transporter binding potential, as measured by positron emission tomography (PET), and amygdala activation, measured by functional magnetic resonance imaging (fMRI). These studies have implicated additional genes that were not detected in our studies based solely on the clinical diagnosis, suggesting other biological pathways that may be involved in mood disorders. Ongoing work is aimed at correlating our findings with those of other genome-wide association studies, studying the genes that seem to play the biggest role in disease risk, and identifying genes that help shape the clinical picture and response to treatment. We have also begun to explore multi-locus models that may better capture the multi-genic nature of this complex genetic disorder.